Welcome, myeloma world, to the first "Acronym Edition" of Myeloma Morning.

Every major news item in today's report is closely linked with one or more acronyms. Once we realized this – and once we also realized that this will probably happen again in the future – we realized we had to mark the occasion in some special way.

Hence: Acronym Edition.

We have three brief research summaries at the beginning of today's report, followed by an extended Q&A.

The first two research summaries are mainly for readers interested in the biology of multiple myeloma. One concerns the enzyme MMSET and multiple myeloma with the t(4;14) chromosomal abnormality. The other concerns insulin-like growth factor (IGF) proteins and the role they may play in the development and spread of multiple myeloma.

The third study investigates whether some of the tests regularly done in multiple myeloma patients are being carried out too frequently.

As for the Q&A we have for you, it is the first installment in a multi-part review we'll be doing of the myeloma-related presentations and discussions at this year's annual meeting of the European Society for Blood and Marrow trans­planta­tion (EBMT).

The 2016 EBMT meeting took place earlier this month, and the current president of the EBMT, Dr. Mohamad Mohty, has been kind enough to share with us his perspectives on the meeting. His feedback in today's report focuses on results of the important IFM2009 clinical trial, which is investigating the role of stem cell transplants in newly diagnosed multiple myeloma patients.

Finally, we want to mention that the list of new research articles at the end of our report includes two articles about primary plasma cell leukemia. One article is a report on the results of a Phase 2 clinical trial, and the other article is an editorial about the trial results. Both articles were just published in the Journal of Clinical Oncology, and they are available online at no cost. Although we are not planning to summarize the articles, we wanted to be sure to call attention to them.

MMSET And T(4;14) In Multiple Myeloma

A group of American and Canadian researchers have published a study investigating the role of the enzyme MMSET in multiple myeloma. Their research provides insight into how the t(4;14) chromosomal abnormality may affect the sensitivity of multiple myeloma cells to treatment (abstract).

Previous research has shown that myeloma patients with the t(4;14) chromosomal abnormality have elevated levels of MMSET in their myeloma cells. It also is known that myeloma patients with t(4;14) tend to relapse more quickly than other patients after treatment with drugs such as melphalan, which cause DNA damage in cancer cells. This suggests that MMSET may play a role in how cancer cells respond to and repair DNA damage.

When the American and Canadian researchers added a DNA-damaging agent to myeloma cell lines with high levels of MMSET, the cells repaired DNA damage at an enhanced rate and continued to proliferate. On the other hand, when a DNA-damaging agent was added to myeloma cell lines with low levels of MMSET, DNA damage accumu­lated and the cells stopped reproducing.

The researchers observed a similar effect when they used a mouse model. Depleting MMSET in the mice enhanced the efficacy of chemotherapy, inhibiting tumor growth and extending survival.

The researchers conclude that “These findings help explain the poorer prognosis of t(4;14) multiple myeloma and further validate MMSET as a potential therapeutic target in multiple myeloma and other cancers.”

Insulin-Like Growth Factor (IGF) In MGUS And Multiple Myeloma

A new study out of Denmark provides valuable insights for researchers investigating the role of proteins known as insulin-like growth factors (IGFs) in the biology of multiple myeloma (full text).

There are two insulin-like growth factors, IGF1 and IGF2, which are molecules similar to insulin. There also are six proteins known as insulin-like growth factor binding proteins (IGFBPs). As their name suggests, IGFBPs bind to IGF1 and IGF2. There are six IGFBPs, identifed as IGFBP1 through IGFBP6.

The Danish researchers were motivated by previous research showing that IGF1 plays a role in the growth, survival, and spread of multiple myeloma cells. There also has been research suggesting a link between IGF1 levels in the blood and prognosis in multiple myeloma patients.

Thus, the Danish researchers set out to measure the levels of IGF1, IGF2, and select IGFBPs in both blood samples and bone marrow samples. They drew the blood and marrow samples from three groups of people: people who are healthy; people with monoclonal gammopathy of undetermined significance (MGUS); and people who have multiple myeloma.

The details of what the Danish researchers found are not particularly important for our discussion here. What is important, however, is that, based on their findings, the researchers were able to develop a schematic of how the levels of these proteins change as people go from being healthy, to having MGUS, and then to having multiple myeloma (Figure 3 in the the researcher's paper).

This schematic provides insights into the role IGF-related proteins may play in the biology of multiple myeloma while, at the same time, highlighting issues and questions that will need to be addressed by future research.

Protein Testing In MGUS And Myeloma Patients

The last study that we look at today before we turn to our extended Q&A is from researchers at the Medical College of Georgia at Augusta University. It concerns the protein testing that is regularly carried out in MGUS and multiple myeloma patients to measure markers such as a patient's M-spike and free light chain levels (abstract).

The Georgia researchers conducted a review of serum protein electrophoresis (SPEP), serum immuno­fixa­tion electro­phoresis (IFE), and serum free light chain (sFLC) tests carried out in their treatment center over a two-month period in 2014. They then assessed to what extent all the tests were necessary.

Based primarily on the assumption that SPEP test results are the most critical test for monitoring MGUS and multiple myeloma, the authors conclude that less than half the IFE and sFLC tests that were carried out were necessary. They then calculate the cost savings that could have been achieved by eliminating the potentially unnecessary IFE and sFLC tests. They also propose an algorithm for determining whether IFE and sFLC tests should be ordered for a patient.

We suspect that most myeloma specialists and patients will take issue with the authors' findings.

Multiple Myeloma At The 2016 EBMT Meeting

We end our report today with an extended Q&A with myeloma and stem cell transplant specialist Dr. Mohamad Mohty, current president of the European Society for Blood and Marrow Transplantation (EBMT).  Dr. Mohty is professor of hematology and head of the hematology and cellular therapy department at the Saint-Antoine Hospital and University Pierre & Marie Curie in Paris, France.

Each year, the EBMT holds an annual meeting at which a substantial amount of new multiple myeloma-related research is presented. The 2016 EBMT meeting was earlier this month, so we thought we would check in with Dr. Mohty to get his feedback on what happened at the meeting.

We will be sharing Dr. Mohty's feedback over the course of several editions of Myeloma Morning. Here is the first installment in the Q&A.

Before we discuss the multiple myeloma-related highlights of this year's EBMT meeting, Dr. Mohty, can you tell us more about what the EBMT is?

Dr. Mohty – The European Society for Blood and Marrow Trans­planta­tion (EBMT) is a non-profit organi­za­tion that was established in 1974 in order to allow scientists and physicians involved in clinical bone marrow and stem cell trans­planta­tion to share their experience and develop cooperative studies. The EBMT is devoted to the promotion of all aspects associated with the trans­planta­tion of hemato­poietic stem cells from all donor sources and donor types including basic and clinical research, education, standardization, quality control, and accreditation for transplant procedures.

Can you set the stage for us a bit in terms of when and where the 2016 EBMT meeting was held, and how it was organized?

Dr. Mohty – The EBMT held its 42nd annual meeting in Valencia, Spain, on April 3 through April 6, 2016. The meeting was attended by almost 5000 health care professionals (physicians, nurses, pharmacists, and scientists). This edition of the meeting included a record number of satellite symposia, educational lectures and workshops, a lunch debate, nursing sessions, and other “meet the expert” sessions dedicated or focused on multiple myeloma. The opening lecture of the meeting – which is the most prestigious lecture of the meeting – was delivered by Prof. Jesús San Miguel and was entitled “Multiple Myeloma: Evolution in the Treatment Landscape”. Most aspects of myeloma management and therapy were addressed by experts in the field.

We understand that an important topic at the meeting was the role of stem cell trans­planta­tion in the initial treatment of multiple myeloma patients. Is that true?

Dr. Mohty - Yes, the role of autologous stem cell trans­planta­tion frontline for young and fit patients was debated extensively during a non-for-profit symposium supported by the “Intergroupe Francophone du Myélome” (IFM) and during an exciting lunch debate between Prof. Jean-Luc Harousseau (Nantes, France) and Prof. Paul Richardson (Boston, Massachusetts). During the IFM symposium, the interim results of the IFM2009/DFCI randomized trial were presented, including results assessing the impact of minimal residual disease (MRD) measurement as part of this trial.

Can you tell us more about the rationale for the IFM2009/DFCI trial and its goal?

Dr. Mohty – The background behind the launch of this trial was that autologous stem cell trans­planta­tion has been considered over the last 20 years as the standard of care for newly diagnosed myeloma patients younger than 65 years of age. However, the high complete response rate achieved with the triplet combination of immunomodulatory drugs (such as Revlimid and thalidomide), proteasome inhibitors (such as Velcade and Kyprolis), and dexamethasone has led some investigators to question the role of autologous trans­planta­tion frontline.

Therefore, the aim of this trial was to determine if, in the era of new drugs, transplant was still necessary in the initial management of young patients.

The goal of the trial was reflected, of course, in its design. Here is a quick summary of the design.

Participants in the IFM 2009 trial were randomly assigned to one of two trial arms – a “transplant arm” and a “non-transplant arm”.

In both arms, patients initially received three cycles of Velcade, Revlimid, and dexamethasone followed by stem cell mobilization and harvesting.

After mobilization, patients in the transplant arm had their stem cell transplant, followed by two more cycles of Velcade, Revlimid, dexamethasone as consolidation therapy, and then one year of Revlimid maintenance therapy.

In the non-transplant arm, patients after mobilization received five more cycles of Velcade, Revlimid, and dexamethasone, followed by 12 months of Revlimid maintenance.

Can you tell us, Dr. Mohty, what the primary and secondary objectives of the trial were?

Dr. Mohty - The primary objective was to compare progression-free survival (PFS) between the two study arms, while the secondary objectives were to compare response rate, MRD status (by flow cytometry), time to progression, overall survival, and toxicity between the two arms.

What were the eligibility criteria for the trial, and how many patients took part?

Dr. Mohty – Trial participants had to be newly diagnosed multiple myeloma patients, aged between 18 and 65 years, and in good general health (an ECOG performance status less than 2). Patients needed to have symptomatic myeloma with organ damage related to myeloma, and measurable disease (serum M-protein greater than 10 g/l = 1 g/dL, and/or urine M-protein greater than 200 mg/24 h, and/or involved serum free light chain level greater than 100 mg/l provided the serum free light chain ratio is abnormal).

A total of 69 centers in France, Belgium, and Switzerland enrolled 764 patients (700 randomized) between November 2010 and November 2012. There were two pre-specified interim analyses: the first interim analysis (33% of events) was in March 2014, and the second interim analysis (69% of events) was in June 2015. With a median follow-up of 39 months, the independent data monitoring committee (DMC) recommended stopping the trial.

What were the key results of the study, and what did investigators conclude?

Dr. Mohty - As expected, patients’ and disease characteristics were balanced between the two arms. The trial reached its primary endpoint showing a significantly higher progression-free survival (PFS) in the transplant arm compared to the non-transplant arm (median PFS 43 versus 34 months; hazard ratio: 0.69; p<0.001 as of September 2015 – non-final analysis). Moreover, the transplant arm was associated with an increased rate of MRD negative status (80 percent versus 65 percent, p<0.01).

Overall, this second interim analysis demonstrated that autologous trans­planta­tion was feasible in 93% of cases, and associated with an acceptable transplant-related mortality (1.4 percent) and improved 4-year PFS (47 percent vs 35 percent, p<0.001).

However, one should note that a longer follow up is still required to draw a firm conclusion concerning overall survival, since the 4-year overall survival was high and comparable in both the transplant and non-transplant arms (81 percent versus 83 percent, respectively; p=NS).

Based on these findings, the investigators concluded that autologous stem cell trans­planta­tion should remain the standard of care for young and fit patients frontline even in the era of modern treatment combinations, and despite the lack of an overall survival difference.

Thank you, Dr. Mohty. We look forward to continuing our discussion of these trial results, as well as other presentations at this year's EBMT meeting, in another upcoming edition of Myeloma Morning.

New Myeloma-Related Research Articles

1. Bieghs, L. et al., “Abnormal IGF-binding protein profile in the bone marrow of multiple myeloma patients” in PLoS One, April 25, 2016 (full text)
2. Heaton, C, Vyas, S. G., Singh, G., “Audit of use and overuse of serum protein immunofixation electrophoresis and serum free light chain assay in tertiary health care: a case for algorithmic testing to optimize laboratory utilization” in the American Journal of Clinical Pathology, April 22, 2016 (abstract)
3. Musto, P. Y., “Progress in the treatment of primary plasma cell leukemia” in the Journal of Clinical Oncology, April 25, 2016 (full text)
4. Royer, B. et al., “Bortezomib, doxorubicin, cyclophosphamide, dexamethasone induction followed by stem cell trans­planta­tion for primary plasma cell leukemia: a prospective phase II study of the Intergroupe Francophone du Myélome” in the Journal of Clinical Oncology, April 25, 2016 (full text)
5. Shah, M. Y. et al., “MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents” in Oncogene, April 25, 2016 (abstract)